IE42630B1 - Dithia-tetraazacyclooctane-tetraoxide - Google Patents

Abstract

1463261 1,5 - Dithia - 2,4,6,8 - tetraazacyclooctane-1,1,5,5-tetraoxides CHEM PHARMAZ FABRIK DR HERMANN THIEMANN GmbH 2 June 1975 [24 Feb 1975] 23845/75 Heading C2C [Also in Division A5] Novel therapeutic compounds (I) where each R is MeSO 2 and each R1 is H or each R and each R1 are Cl, are made by reacting H 2 N-SO 2 -NH 2 with RCH(R1)CHO or a dialkyl acetal thereof in concentrated acid.

Description

This invention relates to the use of 1,5 - dithia2,4,6,8 - tetraaza - cyclooctane - 1,1,5,5 - tetraoxides of the general formula I \s° R I R—CH HN HN >/ z x o o i lx \_A ./ wherein each R denotes a chlorine, bromine or iodine atom or a methylsulphonyl group and each R^ denotes a hydrogen atom, or each R and each R1 denotes a chlorine atom.

These compounds have been found to have a bacteriostatic, bactericidal, virostatic, cytostatic and/or immunosuppressive action, and to be useful in pharmaceutical preparations and as disinfectants for external use, for example for disinfecting equipment and rooms.

The invention therefore provides a pharmaceutical preparation comprising a compound of the general formula I as defined above, in admixture or conjunction with a pharmaceutically suitable carrier.

The pharmaceutical preparation is preferably administered orally or intravenously.

The pharmaceutical preparations may be formulated in a conventional manner into unit dosage form, for example into tablets, dragees, capsules, syrups, suppositories, injections, ointments, creams, lotions and gels.

The dosage units and the daily doses are preferably as follows; Unit dose oral: 5—50 mg Unit dose intraveneous: 2—25 mg Daily dose oral: up to 200 mg Daily dose intravenous: up to 100 mg The invention also provides a disinfectant which comprises a compound of the general formula I as defined above in admixture with a diluent.

It has been found that the disinfecting effect especially against Gram-negative germs, may be intensified when the disinfectant also comprises an aldehyde, for example formaldehyde or glyoxal.

Compounds of the general formula I in which each R denotes a methylsulphonyl radical and each R1 denotes a hydrogen atom or in which each R and each R3 denotes a chlorine atom are novel. The invention, therefore, provides such compounds.

A compound of the general formula I may be manufactured by treating sulphamide of the formula II h2n—so2—NH2 (IX) with an acetaldehyde of the general formula III R1XH I / R—CH—C (III) X or a dialkyl acetal thereof in which each alkyl moiety has up to 6 carbon atoms, in a concentrated acid, for example a concentrated mineral acid, preferably concentrated hydrochloric acid. Advantageously, the reaction is carried out at room temperature, whilst stirring. The alkyl radicals in the acetal preferably have up to 4 carbon atoms, and an ethyl acetal or a methyl acetal is particularly preferred.

The following Examples 1 to 4 illustrate the preparation of compounds of the general formula I. Examples 5 to 10 illustrate the preparation of pharmaceutical preparations in unit dosage form, and Example 11, the preparation of a disinfectant.

Example 1 0.01 mole of sulphamide in 5 ml of concentrated hydrochloric acid are added to 0.012 mole of chloroacetaldehyde, at room temperature whilst stirring. After 5 minutes, the precipitate which has formed is filtered off and washed with ice water, dried and reerystallised from acetone/petroleum ether. 3,7 - Di - (chloromethyl) - 1,5 - dithia - 2,4,5,8 - tetraazacyclooctane - 1,1,5,5 - tetraoxide is obtained as colourless crystals of melting point 175°C (decomposition) in a yield of 70% of the theoretical yield.

Example 2 0.01 mole of sulphamide in 5 ml of concentrated hydrochloric acid is added to 0.012 mole of bromoacetaldehyde - diethylacetal, at room temperature whilst stirring. After 5 minutes, the precipitate which has formed is filtered off and washed with ice water, dried and recrystallised from acetone/ petroleum ether. 3,7 - Di - (bromomethyl) - 1,5 - dithia2,4,6,8 - tetraaza - cyclooctane - 1,1,5,5 - tetraoxide is obtained as colourless needle-shaped crystals of melting point 172°C (decomposition) in a yield of 60%.

When bromoacetaldehyde - dimethylacetal is used the yield is somewhat higher.

Example 3 By a method analogous to that described in Example 2, 3,7 - di - (iodomethyl) - 1,5 - dithia - 2,4,6,8 - tetraazacyclooctane - 1,1,5,5 - tetraoxide is obtained, as colourless needle-shaped crystals of melting point 162°C (decomposition), in a yield of 40%, from iodoacetaldehyde - diethylacetal and sulphamide.

Example 4 3,7 - Di - (dichloromethyl) - 1,5 - dithia - 2,4,6,8tetraazacyclooctane - 1,1,5,5 - tetraoxide is obtained by a method analogous to that described in Example 2. It shows discolouration above 180°C; and has a melting point of 212°C (decomposition).

Example 5 Tablets/Dragees 3,7-Di-(chloromethyl)-5-dithia2,4,6,8-tetraaza-cyclooctane1,1,5,5-tetraoxide 20 mg Lactose 30 mg Corn starch 17 mg Talc 3 mg The active substance and lactose are granulated with isopropanol, the granules are mixed intensively with the remaining constituents and the mixture is pressed to give tablets or dragee cores. The cores are made into dragees by customary processes. 630 Example G Injection solution 3,7-Di(bromomethyl)-1,5-dithia 2,4,6,8-tetraaza-cyclooctane1,1,5,5-tetraoxide Polyethylene glycol, molecular weight 200 mg 750 mg to 3.0 ml Isotonic NaCl solution The finely powdered active substance is dissolved in the 30% strength polyethylene glycol solution, whilst warming slightly and stirring, and after cooling the solution is made up to 3.0 ml with Isotonic NaCl solution. The ampoules are sterile-filtered or sterilised.

Example 7 Ointment Active substance according to Example 6 1.0 g Liquid paraffin 3.0 g White petroleum jelly to 100.0 g The active substance is triturated with the paraffin and then dispersed in the white petroleum jelly at ambient temperature.

Example 8 Cream Active substance according to Example 6 1.0 g Liquid paraffin 32.0 g Cetyl alcohol 3.0 g Anhydrous lanolin 10.0 g Cationic, complex, higher-alkylamine as softener 2.0 g Non-ionic sorbitane fatty acid ester as stabiliser 2.0 g Polyoxyethylene-sorbitane monostearate 3.0 g Preservative 0.2 g Distilled water 46.8 g The active substance is dissolved in a small amount of water or triturated with a small amount of liquid paraffin. Cetyl alcohol is melted with lanolin; liquid paraffin, softener, stabiliser and polyoxyethylene - sorbitane monostearate are added to the melt and the mixture is dissolved in the solution of the preservative in water at ambient temperature until a cream-like mass has formed. The solution or triturated form of the active substance is then admixed with the cream.

. Example 9 Lotion .

Active substance according to Example 6 1.0 g 94.6% strength ethanol 15.0 g Diethylene glycol monoethyl ether 3.0 g Citric acid 0.2 g Distilled water 77.8 g Glycerol 3.0 g The active substance is dissolved in water or in the diethylene glycol monoethyl ether/ethanol mixture. Citric acid is dissolved in a small amount of water. The alcoholic phase and the aqueous phase are mixed together, glycerol is added and the lotion is mixed thoroughly.

Example 10 Gel Active substance according to Example 6 1,0 g Carboxymethylcellulose (highly etherified) 2.0 g Glycerol .0 g 94.6% strength ethanol 17.0 g Distilled water 50.0 g The active substance is dissolved in ethanol or water.

The carboxymethylcellulose is triturated with glycerol and left to swell in water. The two phases are then homogeneously mixed.

Example 11 g of 3,7 - di - (bromomethyl) - 1,5 - dithia - 2,4,6,8 tetraaza - cyclooctane - 1,1,5,5 - tetraoxide is dissolved in 2,000 ml of water and surfaces are sprayed with this solution. The germa present on the surface (for example Staphylococcus aureus haemolyt. (micrococcus pyogenes), Pseudomonas, Coli bacteria and Blastomyces) are killed within I to 2 hours.

The active substance may alternatively be dissolved in dilute ethanol or isopropanol, instead of in water.

Claims (22)

1. A pharmaceutical preparation which comprises a compound of the general formula R' ,1 HN NH ,1 R· wherein each R denotes a chlorine, bromine or iodine atom or a methyl sulphonyl radical and each R denotes a hydrogen atom, or each R and each R 3 denotes a chlorine atom, in admixture or conjunction with a pharmaceutically suitable carrier.

2. A pharmaceutical preparation which comprises a compound of the general formula given in claim 1, wherein each R denotes a methyl sulphonyl radical and each R 1 denotes a hydrogen atom, or each R and each R 4 denote chlorine atoms, in admixture or conjunction with a pharmaceutically suitable carrier. .

3. A preparation as claimed in claim 1 or claim 2, in unit dosage form.

4. A preparation as claimed in any one of claims 1 to 3, in a form suitable for oral administration.

5. A preparation as claimed in claim 4 when appended to claim 3, which comprises from 5 to 50 mg of the cited compound per unit dose.

6. A preparation as claimed in any one of claims 1 to 3, in a form suitable for intravenous administration.

7. A preparation as claimed in claim 6 when appended to claim 3, which comprises from 2 to 25 mg of the cited compound per unit dose.

8. A preparation as claimed in claim 1 or claim 2, in the form of a tablet, dragee, capsule, syrup, suppository, injection, ointment, cream, lotion or gel.

9. A preparation as claimed in claim 1, substantially as described in any one of Examples 5 to 10 herein.

10. A disinfectant which comprises a compound of the general formula defined in claim 1, in admixture with a diluent.

11. A disinfectant which comprises a compound of the general formula defined in claim 2, in admixture with a diluent

12. A disinfectant as claimed in claim 10, which additionally comprises an aldehyde.

13. A disinfectant as claimed in claim 12, wherein the aldehyde is formaldehyde or glyoxal.

14. A disinfectant as claimed in claim 10, substantially as described in Example 11 herein.

15. A 1,5 -dithia - 2,4,6,8 - tetraaza - cyclooctane1,1,5,5 - tetraoxide of the general formula wherein each R denotes a methylsulphonyl radical and each R 1 denotes a hydrogen atom, or each R anti each R^ denote chlorine atoms.

16. 3,7 - Di - (dichloromethyl) - 1,5 - dithia - 2,4,6,8 tetraaza - cyclooctane - 1,1,5,5 - tetraoxide.

17. A process for the manufacture of a compound as claimed in claim 15, which comprises treating sulphamide with an acetaldehyde of the general formula - 10 42630 R 1 ri I R—CH—C in which R and R 1 are defined as in claim 15, or a dialkyl acetal thereof, in which each alkyl moiety has up to 6 carbon atoms, in a concentrated mineral acid. 5

18. A process as claimed in claim 17, wherein the reaction is carried out at room temperature whilst stirring.

19. A process as claimed in claim 17 or claim 18, wherein a dialkyl acetal of the aldehyde is used in which each alkyl moiety has up to 4 carbon atoms. 10

20. A process as claimed in claim 19, wherein an ethyl acetal or methyl acetal of the aldehyde is used.

21. A process as claimed in claim 17, carried out substantially as described in Example 4 herein.

22. A compound as claimed in claim 15, whenever prepared 15 by a process as claimed in any one of claims 17 to 19.